J. Braz. Chem. Soc. vol.22 número9

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Article

A

*e-mail: haobozhang1980@gmail.com, zxh7954@hotmail.com

Novel Chiral Ionic Liquid (CIL) Assisted Selectivity Enhancement to (L)-Proline

Catalyzed Asymmetric Aldol Reactions

Long Zhang, Haibo Zhang,* Huadong Luo, Xiaohai Zhou* and Gongzhen Cheng

College of Chemistry, Wuhan University, 430072, P. R. China

Melhoras signiicativas nos rendimentos químicos (até 88%), estereosseletividades (> 99:1) e excessos enantioméricos (até 98%) foram observadas em reações aldólicas assimétricas catalisadas por (L)-prolina, quando líquidos iônicos quirais baseados em prolina (CILs) foram usados como aditivos. Diferentes proporções de DMSO/H2O como solvente, e líquidos iônicos quirais (CILs)

com cátions quirais com diferentes comprimentos de cadeia, foram investigados.

A signiicant improvement of the chemical yields (up to 88%), stereoselectivity (> 99:1) and enantiomeric excesses (up to 98%) of (L)-proline catalyzed direct asymmetric aldol reaction was found when proline based chiral ionic liquids (CILs) were added as additives. Different ratios of DMSO/H2O as solvent and chiral ionic liquids (CILs) with chiral cations of different chain length

were investigated.

Keywords: aldol reaction, asymmetric synthesis, chiral ionic liquids, chiral additive

Introduction

Room temperature ionic liquids (RTILs) including chiral ionic liquids (CILs) have received growing attentions both from theoretical research and actual productions due to their tuneable features for various chemical tasks and their advantages as homogeneous support, reaction

media, etc.1,2_{Since the irst example of chiral ionic liquid}

reported by Howarth et al.3_{in 1997, a large number of CILs}

bearing chiral cations, anions or seldom both were reported

by other groups.4,5_{Previous studies have shown that in}

many asymmetric reactions the use of CILs as reaction media or catalyst can enhance the yield and/or selectivity

significantly.6-8_{As most of the asymmetric reactions}

were carried out using metal/chiral catalysts as chiral sources, which are relatively expensive or environmental unfriendly, searching for a catalyst which is easy to obtain and environmentally benign for the asymmetric reactions is of great signiicance. In our previous work, a series of

(L)-proline based CILs were proved to have the potential

to provide a strong chiral environment by 19_{F NMR study.}9

In this article, a series of reactions were carried out to

investigate the catalytic properties of these (L)-proline

based CILs, and very high chiral selectivity was obtained.

Aldol reaction has been a typical asymmetric reaction used in the search of efficient asymmetric catalyst, especially for environmental friendly and metal-free

organic catalyst.10-13_{Since CILs used as catalyst in}

aldol reaction by Luo et al.14 _{in 2007, many CILs were}

developed as catalysts for asymmetric reactions. However, in asymmetric reactions where CILs cannot be applied as catalysts, using CILs as the solvent to investigate the chiral inducing capabilities has rarely been reported. Here we chose the asymmetric aldol reactions as our initial focus to examine the applications of CILs in asymmetric reactions.

(L)-Proline and its structural analogs were found to be good

catalyst for aldol reaction,15-19_{and (}_L_{)-proline combined}

with ILs were also proved to be an eficient catalytic

system for asymmetric aldol reactions.20-23_{However, a}

systematic study about the relationship between structure and properties of ionic liquids is of great interest to many researchers.

Results and Discussion

In this work, (L)-proline based CILs (Scheme 1)

are used as chiral additives for (L)-proline-catalyzed

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Zhang et al. 1737 Vol. 22, No. 9, 2011

vacuum for 3 h for the next cycle. The catalytic activity of the catalyst and CILs can be kept after 3 cycles, with only

a slight decrease in ee values. To investigate the generality

of the CILs as additives, a series of aromatic aldehyde acceptors were subjected to the same reaction conditions.

From the results above, an obvious ee enhancement change

can be found when ₋NO2 was in different positions (entries

4 and 5, entries 9 and 10, entries 14 and 15). In details, the

−NO2 in -o and -p position showed better result than that

in the -m position. This is mainly due to the positive effect

in nucleophilic addition by ₋NO2 in -o and -p position.

Furthermore, other aromatic aldehydes with different

substituents at -p positions (entries 16 and 17, entries 18 and

19, entries 20 and 21, entries 27 and 28, entries 29 and 30) were also investigated to validate the results, it can be seen that all of them react well in this catalytic system and almost no signiicant change in selectivity which reveals that substituents have less effect in the chemical selectivity. As for the CILs, their solubility can be adjusted by altering the

alkyl chain. In details, 2a, 2b and 2c have good solubility in

water while the others with longer chain lengths are better miserable with low polarity solvent. The other two kinds of CILs with different (TG) counter ions also have their own unique proprieties. Thermogravimetric measurement reveals

that these CILs have Td (thermal degradation temperature)

in the order of BF4− > Br− > NO3−. Although their widely

different proprieties were shown by different chain lengths and different counter ions, they showed no signiicant change both in chemical yields and selectivity. The mechanism is still under investigation. As temperature is an important factor in most of the asymmetric synthesis, lower the temperature (Table 1, entries 6 and 13) in our system showed only a small

change in ee values (2% and 5%, respectively).

In addition, the aldol reaction between cyclohexanone

and 4-nitrobenzaldehyde in the presence of (L)-proline and

2 in DMSO/H2O solvent was also investigated (Table 2).

Similarly, the reactions were carried out using (L)-proline

as catalyst with or without CILs. It was very interesting to ind that when 10 mol% of CILs was added, the yields, stereo-selectivity and enantiomeric excesses were enhanced signiicantly. The solvent, which is very important in organic reactions, was optimized by a series of comparison

experiments use different ratio of DMSO/H2O (Table 2,

entries 1 to 4). It was found that the best results were

N

H H

COOH _{RBr, K}

2CO3

CH3CN, 70 °C,48 h N

H COOH

R R

MY

CHCl3, r.t., 4 h

N H

COOH

n-C4H9 n-C4H9

Br–

Y– 3a:Y− _{= NO}

3−

3b:Y− _{= BF}

4−

MY= AgNO3, NaBF4

1 2

2a: R = CH2CH3

2b:R = (CH2)3CH3

2c: R = (CH2)5CH3

2d:R = (CH2)7CH3

2e:R = (CH2)9CH3

2f: R = (CH2)11CH3

3

Scheme 1. Synthesis of CILs.

OHC

NO2 O

OH O

O2N

O

O2N 30 mol% (L)-proline

2, 24 h, r.t.

Minor side product

Scheme 2. (L)-proline-catalyzed aldol reaction of aromatic aldehyde with acetone.

of (L)-proline even with a slight amount the reactions

proceeded at room temperature and gave the aldol product. The yields were obviously increased with increasing

amount of (L)-proline (Table 1, entries 2 to 4). When

(L)-proline (30 mol%) and 2b (7.5 mol%) in an acetone

mixture of the reactants were used, the reaction proceeded

with a superior yield (up to 97%) and a moderate ee value

(71%). An obvious decrease of the yield but a slight increase

of the ee values can be observed with decreasing amount

of (L)-proline. This result is in accordance with that of

Jacobsen’s catalytic mechanism.25_{It can be concluded}

that the amount of catalyst have a direct relationship with the yield but a slight inluence on the reaction selectivity. For the CILs, when the amount of CILs varied from 1 mol% to 7.5 mol%, it was found almost no change in the reaction yield, while the by product due to dehydration

increased slightly with the increase of CILs. The ee values

deinitely increased with the addition of CILs 2b, although

very slightly. Using different aromatic aldehyde in the (L

)-proline catalyzed aldol reaction, adding 2b as additive and

as well good yield and selectivity, the enantiomeric excesses can have up to 24% enhancement.

In summary of the results above, the best reaction ratio of catalyst and additives were found to be 30 mol% (L)-proline as catalyst and 7.5 mol% CILs as additives. Based on this founding, all of the following reactions were carried out on these conditions. The recycle ability of the catalyst and CILs were also studied (Table 1, entry 4 f-h). The reaction was taken 24 h, the solvent was evaporated, and

resides were extracted with Et2O three times. The combined

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Novel Chiral Ionic Liquid (CIL) Assisted Selectivity Enhancement J. Braz. Chem. Soc.

1738

Table 1. (L)-Proline-catalyzed aldol reaction of aromatic aldehyde with acetone

entry 4-(R) (L)-Proline /

molar ratio Product

CILs /

molar ratio Conv. / (%)

a _{Selec. / (%)}b _ee_{/ (%)}c

1 4-NO2C6H4 0 5a 7.5% 2b — — —

2 4-NO2C6H4 5% 5a 7.5% 2b 26 95 73

3 4-NO2C6H4 10% 5a 7.5% 2b 64 99 75

4 4-NO2C6H4 30% 5a 7.5% 2b 96 > 99 74

— i _—i ₇₁f

— i _—i ₆₉g

— i _—i ₆₉h

5 4-NO2C6H4 30% 5a 0 97d > 99d 66d

6 4-NO2C6H4 30% 5a 7.5% 2b 97e > 99e 76e

7 4-NO2C6H4 30% 5a 1% 2b 96 98 69

8 4-NO2C6H4 30% 5a 5% 2b 97 96 71

9 2-NO2C6H4 30% 5b 7.5% 2b 98 > 99 79

10 2-NO2C6H4 30% 5b 0 98d > 99d 72d

11 2-NO2C6H4 30% 5b 7.5% 3a 97 > 99 81

12 2-NO2C6H4 30% 5b 7.5% 3b 97 > 99 81

13 2-NO2C6H4 30% 5b 7.5% 2b 53e > 99e 84e

14 3-NO2C6H4 30% 5c 7.5% 2b 93 98 72

15 3-NO2C6H4 30% 5c 0 91d > 99d 68d

16 C6H5 30% 5d 7.5% 2b 85 72 65

17 C6H5 30% 5d 0 80 61 64d

18 4-CH3C6H5 30% 5e 7.5% 2b 84 69 70

19 4-CH3C6H5 30% 5e 0 65[d] 82d 64d

20 4-FC6H4 30% 5f 7.5% 2b 98 > 99 70

21 4-FC6H4 30% 5f 0 98[d] > 99d 67d

22 4-FC6H4 30% 5f 7.5% 2a 97 > 99 70

23 4-FC6H4 30% 5f 7.5% 2c 98 > 99 71

24 4-FC6H4 30% 5f 7.5% 2d 96 > 99 69

25 4-FC6H4 30% 5f 7.5% 2e 98 > 99 70

26 4-FC₆H₄ 30% 5f 7.5% 2f 97 > 99 69

27 4-ClC₆H₄ 30% 5g 7.5% 2b 90 88 71

28 4-ClC₆H₄ 30% 5g 0 85d ₈₈d ₆₈d

29 4-BrC₆H₄ 30% 5h 7.5% 2b 92 89 70

30 4-BrC₆H₄ 30% 5h 0 90d ₈₆d ₆₇d

a_{Based on the aldehyde recovery after column chromatography.}b_{Determined by}1_{H NMR.} c_{Determined by HPLC.}d_{Comparison results with (}_L_{)-proline as} catalyst. e_{The reaction temperature is –15}_°_C.f-h_{Second, third, forth reuse of the CILs and catalysts, respectively.}i_{Not detected.}

CHO

O2N

O _O _OH

NO2

(L)-proline 10 mol%

CILs 10 mol%, solvent, 24 h, r.t.

7

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Zhang et al. 1739 Vol. 22, No. 9, 2011

obtained when the DMSO:H2O = 4:1(Table 2, entry 3).

The other CILs were also used as additives in this catalytic system (Table 2, entries 5 to 9). All of them showed superior co-catalytic effect in aldol reactions.

Conclusions

In summary, a novel asymmetric catalytic system with

N-substituted pyrrolidine-ionic liquids as chiral additives

was developed and their potentials of providing chiral environment by direct asymmetric aldol reaction were demonstrated. This catalytic system can lead to high yields (up to 88%), good stereoselectivities (> 99:1) and superior enantiomeric excesses (up to 98%) for syn-selective aldol reactions. This is the irst use of chiral environment as chiral source to lead asymmetric reaction to our knowledge. Further studies on this kind of CILs in other asymmetric reactions are underway in our laboratory.

Experimental

General procedure for chiral ionic liquid (CILs) synthesis

(L)-Proline (0.1 mol) and 1-bromoalkane (0.3 mol) were

mixed in a 100 mL round bottom lask with acetonitrile as solvent at 70 °C for 2 days in an inert atmosphere. After iltering, the solvent was removed by distillation and the raw products were washed with ether for several times.

After puriied by column chromatography (CHCl3:EtOH =

20:1), the product was dried under vacuum for 5 h to afford

the chiral ionic liquids (CILs) 2a-2f.

2b (0.02 mol) and silver nitrate (or tetraluoroborate

ammonium) (0.02 mol) were stirred at room temperature for 4 h with chloroform as solvent. After iltering, the solvent was distilled off and the desired raw chiral ionic liquids

(CILs) 3a and 3b were obtained. After puriied by column

chromatography (CHCl3:EtOH = 20:1), the product was

dried under vacuum for 5 h to afford the inal chiral ionic

liquids (CILs) 3a and 3b.

Characterization of CILs

CIL 2a

1_{H NMR (300 MHz, D}

2O) d4.19 (dq, 3H, J 21.3, 7.3),

3.63 (ddd, 1H, J 11.6, 7.7, 4.3), 3.28 (dq, 1H, J 14.6, 7.3),

3.17-2.97 (m, 2H), 2.29 (ddd, 2H, J 92.6, 11.4, 6.5),

2.05-2.00 (m, 1H), 1.87 (ddd, 1H, J 19.6, 14.4, 12.9), 1.15 (dd,

6H, J 13.2, 7.1). 13_{C NMR (75 MHz, D}

2O) d12.2, 15.1,

24.2, 30.0, 52.7, 56.4, 65.9, 68.3, 171.4).

CIL 2b

1_{H NMR (300 MHz, D}

2O) d 4.42-4.22 (1 H, m),

4.22-4.03 (2 H, m), 3.80-3.57 (m, 1H), 3.33-2.96 (m, 3H), 2.65-2.21 (m, 1H), 2.15-1.76 (m, 3H), 1.69-1.39 (m, 4H), 1.24

(dtd, 4H, J 14.8, 7.4, 3.1), 0.76 (td, 5H, J 7.3, 2.3). 13_{C NMR}

(75 MHz, D2O) d 15.7, 15.8, 21.3, 22.0, 25.2, 30.0, 30.9,

31.0, 32.6, 58.1, 58.5, 69.7, 70.4, 172.3.

CIL 3a

1_{H NMR (300 MHz, CDCl}

3, TMS) d 0.78-0.92 (m, 6H,

CH3), 1.22-1.38 (m, 4H, CH2), 1.48-1.78 (m, 4H, CH2),

2.02-2.26 (m, 3H, CH2), 2.42-2.56 (m, 1H, CH2), 3.14-3.46

(m, 3H, NCH2), 3.84 (s, 1H, NCH2), 4.14 (t, 2H, J 6 Hz,

NCH2), 4.29 (t, 1H, J 8.4 Hz, CH); 13C NMR (75 MHz,

CDCl3, TMS) d 13.7, 13.8, 19.2, 20.2, 22.5, 28.2, 30.5,

30.5, 55.3, 56.4, 66.9, 67.6, 167.5.

CIL 3b

3, TMS) d 0.68-0.94 (m, 6H,

CH3), 1.14-1.40 (m, 4H, CH2), 1.42-1.80 (m, 4H, CH2),

Table 2. CILs as additives for direct aldol reactions between 4-nitrobenzaldehyde and cyclohexanone

entry Solvent

[DMSO:H₂O]a

No additives Assisted by CILs

Yield / (%)b _dr[syn:anti]c _ee_{/ (%)}d _CILs _{Yield / (%)}b _dr[syn:anti]c _ee_{/ (%)}d

1 95:5 20 95:5 86 2b 60 99:1 93

2 90:10 35 94:6 92 2b 85 > 99:1 97

3 80:20 80 93:7 77 2b 90 > 99:1 98

4 70:30 60 92:8 73 2b 55 98:2 97

5 80:20 2a 85 97:3 98

6 80:20 2c 87 > 99:1 97

7 80:20 2d 85 98:2 97

8 80:20 2e 88 > 99:1 98

9 80:20 2f 86 > 99:1 98

a_{Volume ratio of DMSO and H}

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Novel Chiral Ionic Liquid (CIL) Assisted Selectivity Enhancement J. Braz. Chem. Soc.

1740

1.97-2.24 (m, 3H, CH2), 2.36-2.52 (m, 1H, CH2),

3.06-3.40 (m, 3H, NCH2), 3.79 (d, 1H, J 4.5 Hz, NCH2), 4.12

(t, 2H, J 6.6 Hz, NCH2), 4.20-4.32 (m, 1H, CH); 13C NMR

(75 MHz, CDCl3, TMS) d 13.5, 13.7, 19.1, 19.7, 22.9, 27.9,

28.7, 30.4, 56.1, 56.4, 67.3, 67.4, 168.8.

CIL 2c

3, TMS) d 0.68-0.84 (m, 6H,

CH3), 1.08-1.36 (m, 12H, CH2), 1.44-1.88 (m, 4H, CH2),

2.02-2.21 (m, 3H, CH2), 2.42-2.62 (m, 1H, CH2), 3.13-3.40

(m, 3H, NCH2), 3.71 (s, 1H, NCH2), 4.10 (t, 2H, J 6.6 Hz,

NCH2), 4.26-4.38 (m, 1H, CH);

13_{C NMR (75 MHz, CDCl}

3,

TMS) d 14.0, 14.0, 22.1, 22.5, 22.6, 25.6, 25.9, 26.7, 28.5,

28.6, 31.3, 31.5, 53.7, 53.7, 64.9, 67.0, 168.1.

CIL 2d

3, TMS) d 0.72-0.88 (m,

6H, CH3), 1.05-1.38 (m, 20H, CH2), 1.52-1.94 (m, 4H,

CH2), 2.15 (d, 3H, J 3.9 Hz, CH2), 2.47-2.63 (m, 1H, CH2),

3.13-3.50 (m, 3H, NCH2), 3.52-3.74 (m, 1H, NCH2), 4.14

(75 MHz, CDCl3, TMS) d 14.2, 14.2, 22.1, 22.7, 22.7, 25.9,

25.9, 27.0, 28.5, 28.5, 29.3, 29.3, 29.3, 29.3, 31.8, 31.9, 53.9, 53.9, 66.9, 66.9, 168.1.

CIL 2e

3, TMS) d 0.61-0.74 (m,

6H, CH3), 0.96-1.22 (m, 28H, CH2), 1.40-1.80 (m, 4H,

CH2), 2.03 (d, 3H, J 5.4 Hz, CH2), 2.45 (d, 1H, J 8.1 Hz,

CH2), 3.18-3.39 (m, 3H, NCH2), 3.70 (s, 1H, NCH2), 4.00

(75 MHz, CDCl3, TMS) d 14.3, 14.3, 22.0, 22.8, 22.8,

26.0, 26.0, 27.1, 28.6, 28.6, 29.2, 29.2, 29.4, 29.4, 29.7, 29.7, 29.7, 29.7, 32.0, 32.0, 53.3, 53.3, 67.0, 67.0, 167.9.

CIL 2f

3, TMS) d 0.78-0.97(m, 6H,

CH3), 1.05-1.40(m, 36H, CH2), 1.48-1.98(m, 4H, CH2),

1.98-2.42(s, 3H, CH2), 2.60(s, 1H, CH2), 3.06-3.38(m, 3H,

NCH2), 3.64(s, 1H, NCH2), 4.04-4.18(m, 3H, NCH2, CH),

4.20-4.29(m, 1H, CH); 13_{C NMR (75 MHz, CDCl}

3, TMS)

d 14.3, 14.3, 22.3, 22.8, 22.8, 26.0, 26.0, 26.9, 29.2, 29.2,

29.4, 29.4, 29.4, 29.4, 29.7, 29.7, 29.7, 29.7, 32.0, 32.0, 54.4, 54.4, 67.2, 67.2, 168.1.

General procedure for the aldol reactions

(L)-Proline (30 mol%) and the aromatic aldehyde

(1 mmol) were added in the acetone (3 mL); after stirred for 1 min, chiral ionic liquids (CILs) (7.5 mol%) were added and the reaction mixture was stirred at room temperature

(25 °C (± 3 °C)) for 24 h. The acetone was evaporated, the residue was extracted with diethyl ether (3 mL, three times), separated diethyl ether layer was collected, the residues were dried under vacuum at 40 °C during 5 h for the next cycle, the collected solvent was evaporated and

the residues puriied by chromatography on SiO2-column

(Petroleum ether:EtOAc = 3:1). All reaction products had the physical constants and NMR spectra in accord with the published data. The petroleum ether used was of boiling range 60-80 °C. Evaporation of solvent was performed at

reduced pressure at 25 (±3) _°C.

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF ile.

Acknowledgments

We thank Dr. Zhi-Yong Xue (Wuhan University, Wuhan, China) for help in the HPLC analysis and the National Natural Science Foundation of China (Grant Number: 20972120).

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Submitted: February 21, 2011

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Supplementary Information

S

I

*e-mail: zxh7954@hotmail.com

Novel Chiral Ionic Liquid (CIL) Assisted Selectivity Enhancement to (

L

)-Proline

Catalyzed Asymmetric Aldol Reactions

Long Zhang, Haibo Zhang,* Huadong Luo, Xiaohai Zhou* and Gongzhen Cheng

College of Chemistry, Wuhan University, 430072, P. R. China

General remarks

1_{H NMR spectra were recorded on a VARIAN Mercury}

300 MHz spectrometer or VARIAN Mercury 600 MHz spectrometer. Chemical shifts are reported in ppm with the TMS as internal standard. The data are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, brs = broad singlet, coupling constant(s) in Hz,integration). 13_{C NMR spectra were}

recorded on a VARIAN Mercury 75 MHz or VARIAN

Mercury 125 MHz spectrometer. Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. Commercially obtained reagents were used without further puriication. All reactions were monitored by TLC with silicagel-coated plates. Enantiomeric ratios were determined by HPLC, using

a chiralpakAS-H column, a chiralpak AD-H column or

a chiralcel OD-H column with hexane and i-PrOH as solvents. The conigurations were assigned by comparison of the t_R with the reported data.1,2

Characterization of CILs

Figure S1.1_{H NMR (300 MHZ, D}

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Novel Chiral Ionic Liquid (CIL) Assisted Selectivity Enhancement to (L)-Proline J. Braz. Chem. Soc. S2

Figure S2.13_{C NMR (75 MHZ, D}

2O) spectrum of 2a.

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Zhang et al. S3 Vol. 22, No. 9, 2011

Figure S4.1_{H NMR (300 MHZ, D}

2O) spectrum of 2b.

Figure S5.13_{C NMR (75 MHZ, D}

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Figure S6. ESI-Mass spectrum of 2b.

Figure S7.1_{H NMR (300 MHZ, CDCl}

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Figure S8.13_{C NMR (75 MHZ, CDCl}

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3) spectrum of 2c.

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Figure S12. ESI-Mass spectrum of 2c.

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3) spectrum of 2d.

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3) spectrum of 2e.

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Figure S18. ESI-Mass spectrum of 2e.

(18)

3) spectrum of 2f.

3) spectrum of 5a.

Characterization of aldol products

NMR data

All available reagents and solvents were used without further puriication. 1_{H NMR and} 13_{C NMR spectra were conducted}

(19)

3) spectrum of 5a.

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3) spectrum of 5b.

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3) spectrum of 5c.

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3) spectrum of 5d.

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3) spectrum of 5e.

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3) spectrum of 5f.

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3) spectrum of 5g.

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3) spectrum of 5h.

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3) spectrum of 7.

HPLC conditions for the aldol products

4-Hydroxy-4-(4-nitrophenyl) butan-2-one (5a)

The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:30]; low rate 1.0 mL min-1_{; λ= 210 nm; major: t}

R = 12.8 min and

minor: tR =16.8 min.

4-Hydroxy-4-(2-nitrophenyl) butan-2-one (5b)

The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:30]; low rate 1.0 mL min-1_{; λ= 220 nm; minor: t}

R =8.3 min and

major: tR =11.2 min.

4-Hydroxy-4-(3-nitrophenyl) butan-2-one (5c)

The optical purity was determined by HPLC on chiralpak OJ-H column [hexane:2-propanol, 70:30]; low rate 1.0 mL min-1_{; λ= 220 nm; major: t}

R = 10.7 min and

4-Hydroxy-4-phenylbutan-2-one (5d)

The optical purity was determined by HPLC on chiralpak AD-H column [hexane:2-propanol, 95:5]; low

rate 1.0 mL min-1_{;λ= 210 nm; major: t}

R =14.4 min and

minor: tR = 16.3 min.

OH O

O2N

OH O

NO2

OH O

NO2

(28)

(R)-4-Hydroxy-4-p-tolylbutan-2-one (5e)

The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 85:15]; low rate 1.0 mL min-1_{;λ= 220 nm; major: t}

R =9.8 min and

4-(4-Fluorophenyl)-4-hydroxybutan-2-one (5f)

The optical purity was determined by HPLC on chiralpak AS-H column [hexane:2-propanol, 70:3]; low rate 1.0 mL min-1_{;λ= 220 nm , major: t}

R =7.1 min and

minor: 7.6 min.

4-(4-Chlorophenyl)-4-hydroxybutan-2-one (5g)

R = 9.0 min and

OH O

H3C

OH O

F

OH O

Cl

4-(4-Bromophenyl)-4-hydroxybutan-2-one (5h)

R =7.0 min and

minor: tR =8.1 min.

(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone (7)

The optical purity was determined by HPLC on chiralpak AD-H column [hexane:2-propanol, 80:20]; low

rate 0.5 mL min-1_{;λ= 220 nm; mimor: t}

R =21.6 min and

22.7, major: tR =24.6 and 31.4 min. OH O

Br

OH O

(29)

HPLC spectra

Figure S39. HPLC spectrum of 5a (racemic).

Figure S40. HPLC spectrum of 5a (Table 1, entry 5).

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Figure S42. HPLC spectrum of 5b (Table 1, entry 9).

Figure S43. HPLC spectrum of 5b (Table 1, entry 10).

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Figure S47. HPLC spectrum of 5d (racemic).

Figure S46. HPLC spectrum of 5c (Table 1, entry 15).

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Figure S48. HPLC spectrum of 5d (Table 1, entry 16).

Figure S49. HPLC spectrum of 5d (Table 1, entry 17).

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Figure S53. HPLC spectrum of 5f (Table 1, entry 20).

Figure S52. HPLC spectrum of 5e (Table 1, entry 30).

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Figure S54. HPLC spectrum of 5f (Table 1, entry 21).

Figure S55. HPLC spectrum of 5g (racemic).

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Figure S59. HPLC spectrum of 5h (Table 1, entry 29).

Figure S58. HPLC spectrum of 5h (racemic).

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Figure S60. HPLC spectrum of 5h (Table 1, entry 30).

Figure S61. HPLC spectrum of 7 (racemic).

Figure S62. HPLC spectrum of 7 (Table 2, entry 5).

References

1. Zhou Y.; Shan Z.; Tetrahedron: Asymmetry2006, 17, 1671.